Design, synthesis and biological evaluation of novel histone deacetylase1/2 (HDAC1/2) and cyclin-dependent Kinase2 (CDK2) dual inhibitors against malignant cancer.

In the current study, we have designed and synthesized a series of novel histone deacetylase1/2 (HDAC1/2) and cyclin-dependent kinase2 (CDK2) dual inhibitors by integrating purine-based pharmacophore into the recognition cap group of CS055. The representative compound 14d with excellent antiproliferative activities towards five solid cancer cells, showed potent inhibitory activities against HDAC1, HDAC2 and CDK2 with IC50 values of 70.7 nM, 23.1 nM and 0.80 µM, respectively. Besides, compound 14d could effectively block the cell cycle in the G2/M phase and induce apoptosis, which might be related to increasing intracellular ROS levels. Importantly, compound 14d exhibited desirable pharmacokinetic (PK) properties with the intraperitoneal bioavailability of 50.8% in ICR mice, and potent in vivo antitumor activity in the HCT116 xenograft model. Therefore, compound 14d could be considered as a promising lead compound for the development of multitargeting anticancer agents.

Discovery of novel cyclin-dependent kinase (CDK) and histone deacetylase (HDAC) dual inhibitors with potent in vitro and in vivo anticancer activity.

In the current study, we reported a series of novel 1-H-pyrazole-3-carboxamide-based inhibitors targeting histone deacetylase (HDAC) and cyclin-dependent kinase (CDK). The representative compounds N-(4-((2-aminophenyl)carbamoyl)benzyl)-4-(2,6-dichlorobenzamido)-1H-pyrazole-3-carboxamide (7c) and N-(4-(2-((2-aminophenyl)amino)-2-oxoethyl)phenyl)-4-(2,6-dichlorobenzamido)-1H-pyrazole-3-carboxamide (14a) with potent antiproliferative activities towards five solid cancer cell lines, showed excellent inhibitory activities against HDAC2 (IC50 = 0.25 and 0.24 nM respectively) and CDK2 (IC50 = 0.30 and 0.56 nM respectively). In addition, compounds 7c and 14a significantly inhibited the migration of A375 and H460 cells. Further studies revealed that compounds 7c and 14a could arrest cell cycle in G2/M phase and promote apoptosis in A375, HCT116, H460 and Hela cells, which was associated with increasing the intracellular reactive oxygen species (ROS) levels. More importantly, compound 7c possessed favorable pharmacokinetic properties with the intraperitoneal bioavailability of 63.6% in ICR mice, and potent in vivo antitumor efficacy in the HCT116 xenograft model. Our study demonstrated that compound 7c provides a promising strategy for the treatment of malignant tumors.

Thioether-based 2-aminobenzamide derivatives: Novel HDAC inhibitors with potent in vitro and in vivo antitumor activity.

Previously, we focused on a series of 2-aminobenzamide-based histone deacetylase (HDAC) inhibitors, compound 9 of which displayed potent HDAC inhibitory activity against HDAC1 and HDAC2, and moderate anti-proliferative activity against several cancer cell lines. In the current study, we have designed and synthesized a series of novel HDAC inhibitors based on thioether moiety with 9 as a lead compound. Representative compounds12 g and 12 h showed apparently potent anti-proliferative activities against five solid cancer cell lines: A549, HCT116, Hela, A375 and SMMC7721, and low cytotoxicity against NIH 3T3 normal cells. Especially, 12 g and 12 h also revealed potent HDAC inhibitory activity against HDAC1, 2 and 3. In addition, the two compounds could arrest cell cycle in G2/M phase and promote cell apoptosis. Moreover, they showed extended inhibition of colony formation and effectively blocked cell migration towards A549 cancer cells. Furthermore, 12 g and 12 h possessed better pharmacokinetic properties than the lead compound 9. Benefiting from these results, we also explored 12 g and 12 h in the A549 xenografts model for in vivo antitumor activity. The in vivo experiment indicated that 12 g and 12 h could evidently augment antitumor activity (TGI = 56.9% and 62.7% respectively).

Design, synthesis and biological evaluation of novel thioquinazolinone-based 2-aminobenzamide derivatives as potent histone deacetylase (HDAC) inhibitors.

A series of novel 2-aminobenzamide derivatives decorated with thioquinazolinone were designed and synthesized as histone deacetylase (HDAC) inhibitors. These derivatives were evaluated for their antiproliferative activities against several human cancer cell lines including A375, Hela, A549, HCT116 and SMMC7721. It's significantly indicated that some inhibitors exhibited potent antiproliferative activities towards all the studied cancer cell lines. Compounds 7a, 4i, 4o, and 4p exhibited higher antiproliferative activities towards three cancer cell lines: A375, A549 and SMMC7721 compared to CS055, MS275, and CI994. Compound 4p showed more than 4000-fold the isoform selectivity for HDAC1 and more than 250-fold selectivity for HDAC2 compared with HDAC6. The molecular docking analysis reasonably explained the HDAC inhibitory activity and isoform selectivity. In addition, compounds 7a, 4i, 4o, and 4p showed potent inhibitory activities in migration assay and colony formation analysis, and also promoted cell apoptosis. Moreover, compounds 7a, 4i, and 4o inhibited the growth of SMMC7721 cells at S phase of the cell cycle. The immunofluorometric analysis indicated that compounds 7a, 4i, 4o, and 4p could increase the acetylation status of H3K9. Furthermore, in vivo anticancer efficacy of compound 4p was assessed in the A549 xenograft models, and 4p demonstrated potent antitumor activity (TGI = 62.5%). This study provided an effective strategy for further development of tumor-targeting therapy.

Design, synthesis and biological evaluation of novel hydroxamates and 2-aminobenzamides as potent histone deacetylase inhibitors and antitumor agents.

Many studies have indicated that histone deacetylase (HDAC) inhibitors are promising agents for the treatment of cancer. With the aim to search for novel potent HDAC inhibitors, we designed and synthesized two series of hydroxamates and 2-aminobenzamides compounds as HDAC inhibitors and antitumor agents. Those compounds were investigated for their HDAC enzymatic inhibitory activities and in vitro anti-proliferation activities against diverse cancer cell line (A549, HepG2, MGC80-3 and HCT116). Most of the synthesized compounds displayed potent HDAC inhibitory activity and antiproliferative activity. In particular, Compound 12a, N-(2-aminophenyl)-4-[(4-fluorophenoxy)methyl]benzamide, was shown to have the most HDAC inhibitory activity (70.6% inhibition at 5 µM) and antitumor activity with IC50 value of as low as 3.84 µM against HepG2 human liver hepatocellular carcinoma cell line, more than 4.8-fold lower than CS055 and 5.9-fold lower than CI994. HDAC isoform selectivity assay indicated 12a is a potent HDAC2 inhibitor. Docking study of 12a suggested that it bound tightly to the binding pocket of HDAC2. Further investigation showed that 12a could inhibit the migration and colony formation of A549 cancer cells. Furthermore, 12a remarkably induced apoptosis and G2/M phase cell cycle arrest in A549 cancer cells. Those results indicated that compound 12a could be a promising candidate for treatment of cancer.

Synergistic Effect of the Combination of Novel Suberoylanilide Hydroxamic Acid Derivatives with Cisplatin on Anti-proliferation of Human Cancer Cells.

A novel, green, and atom-economical boric acid catalyzed direct amidation without the use of any coupling agents for the preparation of suberoylanilide hydroxamic acid (SAHA) and SAHA-based inhibitors targeting anti-proliferation of cancer cells is provided. The new SAHA-based inhibitor B123, when used alone, exhibited higher anti-proliferative activities than SAHA or Cisplatin against a number of human cancer cells. We have examined the effect of combination of these SAHA-based inhibitors with Cisplatin. We found synergistic effects of the combination of SAHA-based inhibitors with Cisplatin over a wide range of concentrations against human liver cancer cells HepG2 and two human lung cancer cell lines H1299 and H460. This synergism leads up to 8-fold of dose reduction for Cisplatin in the combination with our synthesized inhibitor B123 against H1299.

The complete mitochondrial genome of the Neochauliodes fraternus (Megaloptera: Corydalidae).

The mitochondrial genome of Neochauliodes fraternus (Megaloptera: Corydalidae) is a circular molecule of 15,768 bp in length, containing 37 typical mitochondrial genes: 13 protein-coding genes (PCGs), 2 ribosomal RNAs, 22 transfer RNAs and a non-coding AT-rich region. Its gene order and arrangement are identical to the common type found in most insect mitogenomes. All PCGs start with a typical ATN codon except for the ND1 which uses TTG as its start codon; all PCGs terminate in the common stop codon TAA or TAG, except for the COI, COIII, ND3, ND5, ND4 and CYTB which use single T as their stop codons. The non-coding AT-rich region is 1031 bp long, located between rrnS and tRNA(lle) genes. It contains some structures of repeated motifs and microsatellite-like elements characteristic of the megaloptera.

The Complete mitochondrial genome of the Neochauliodes rotundatus (Megaloptera: Corydalidae).

The mitochondrial genome of Neochauliodes rotundatus (Megaloptera: Corydalidae) is a circular molecule of 15,774 bp in length, containing 37 typical mitochondrial genes: 13 protein-coding genes (PCGs), 2 ribosomal RNAs, 22 transfer RNAs and a non-coding AT-rich region. Its gene order and arrangement are identical to the common type found in most insect mitogenomes. All PCGs start with a typical ATN codon except for the ND1 which uses TTG as its start codon; all PCGs terminate in the common stop codon TAA or TAG, except for the COI, COIII, ND3, ND5, ND4 and CYTB which use single T as their stop codons. The 1061 bp non-coding AT-rich region is located between rrnS and tRNA(lle) genes, containing some structures of repeated motifs and microsatellite-like elements characteristic of the Megaloptera insects.

The complete mitochondrial genome of the Pazala timur (Lepidoptera: Papilionidae: Papilioninae).

The complete mitochondrial genome of Pazala timur (Lepidoptera: Papilionodae) is a circular molecule of 15,226 bp in length, containing 37 typical animal mitochondrial genes: 13 protein coding genes, 2 rRNA genes, 22 tRNA genes and a non-coding AT-rich region. Its gene order and arrangement are identical to all other available butterfly mitogenomes. All PCGs initiate with typical ATN codons, except for COI, which is initiated by the CGA codon. Ten PCGs use complete termination codon (TAA), whereas the COI, COII and ND5 genes end with single T. Twelve intergenic spacers (82 bp in total), and 11 overlapping regions (30 bp in total) are dispersed throughout the whole genome. The non-coding AT-rich region is 403 bp long and contains some conserved structures characteristic of the butterfly mitogenomes, such as the motif ATAGA followed by a 13-bp poly-T stretch and a microsatellite-like (AT)12 element preceded by the ATTTA motif.

The complete mitochondrial genome of the Epacanthaclisis banksi (Neuroptera: Myrmeleontidae).

The mitochondrial genome of Epacanthaclisis banksi (Neuroptera: Myrmeleontidae) is a circular molecule of 15,870 bp in length, containing 37 typical mitochondrial genes: 13 protein-coding genes (PCGs), 2 ribosomal RNAs, 22 transfer RNAs and a non-coding AT-rich region. Its gene order and arrangement are identical to the common type found in most insect mitogenomes. All PCGs start with a typical ATN codon except for the COI which uses TTA as its start codon; all PCGs terminate in the common stop codon TAA or TAG, except for the COI, COII, ND3 and ND5 which use single T as their stop codons. The non-coding AT-rich region is 1065 bp long, located between rrnS and tRNAlle genes. It contains some structures of repeated motifs and microsatellite-like elements characteristic of the neuropterids.

The complete mitochondrial genome of the Hybris subjacens (Neuroptera:Ascalaphidae).

The mitochondrial genome of Hybris subjacens (Neuroptera: Ascalaphidae) is a circular molecule of 15,873 bp in length, containing 37 typical animal mitochondrial genes: 13 protein-coding genes (PCGs), 2 ribosomal RNAs, 22 transfer RNAs and a non-coding AT-rich region. Its gene order and arrangement are identical to the common type found in most insect mitogenomes. All PCGs start with a typical ATN codon except for COI and ND1 which use CTT and TTG as their start codon, respectively; all PCGs terminate in the common stop codon TAA or TAG, except for the COI and ND5 which use single T as their stop codons. The non-coding AT-rich region is 1051 bp long, located between rrnS and tRNA(lle) genes. It contains some structures of repeated motifs and microsatellite-like elements characteristic of the neuropterids.